Heteroarylsulfonamide derivatives and pharmaceutical compositions containing them

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which A is methylene or —O—; B is methylene or —O—; G 1 —G 2 —G 3  form a heteroaromatic or heteroaliphatic chain; g is 0, 1 or 2; U is an alkylene chain optionally substituted by one or more alkyl; Q represents a divalent group containing nitrogen atoms; and T is an optionally substituted aryl or heteroaryl group, have utility in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson&#39;s disease, obesity, hypertension, Tourette&#39;s syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer&#39;s disease, senile dementia, obsessive-compulsive behavior, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendrocrine system, stress, and spasticity.

The present invention relates to novel heteroarylsulphonamide compoundswhich have affinity for 5-HT_(1A) and/or D₂-like (D₂, D₃ and D₄sub-types) receptors, to processes for their preparation, topharmaceutical compositions containing them and to their use in thetreatment of central nervous system disorders, for example depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders,Alzheimer's disease, senile dementia, obsessive-compulsive behaviour,panic attacks, social phobias, eating disorders and anorexia,cardiovascular and cerebrovascular disorders, non-insulin dependentdiabetes mellitus, hyperglycaemia, constipation, arrhythmia, disordersof the neuroendocrine system, stress, and spasticity.

The present invention provides compounds of formula I

including enantiomers and pharmaceutically acceptable salts thereof inwhich

A is methylene or —O—;

B is methylene or —O—;

G₁—G₂—G₃ represent —N(R′)—C(R″)═N—, —N═C(R″)—N(R′)—,—N(R′)—C(R″)═C(R′″)—, —C(R′″)═C(R″)—N(R′)—, —N(R′)—N═C(R″)—,—C(R″)═N—N(R′)—, —N(R′)—N═N—, —N═N—N(R′)—, —N═C(R″)—O—, —N═C(R″)—S—,—O—C(R″)═N—, —S—C(R″)═N—, —O—N═C(R″)—, —S—N═C(R″)—, —C(R″)═N—O—,—C(R″)═N—S—, —S—C(R″)═C(R′″)—, —C(R″)═C(R′″)—S—, —O—C(R″)═C(R′″)—,—C(R″)═C(R′″)—O— or —O—C(R′)(R′)—O—;

R′ is H or an alkyl group containing 1 to 3 carbon atoms;

R″ and R′″, which are the same or different, are H; halo; an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo; carboxy; an alkanoyl group containing 1 to 6 carbon atoms; analkoxycarbonyl group in which the alkoxy group contains 1 to 3 carbonatoms; formyl; cyano; or a carbamoyl group or carbamoylmethyl group eachoptionally N-substituted by one or two alkyl groups, which may be thesame or different, each containing 1 to 3 carbon atoms;

g is 0, 1 or 2;

R₁ represents an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo; an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo; halo; or analkylthio group containing 1 to 3 carbon atoms optionally substituted byone or more halo; the substituents represented by R₁ being the same ordifferent when g is 2;

R₂ is H or an alkyl group containing 1 to 3 carbon atoms;

R₃ and R₄, which are the same or different, are H, or an alkyl groupcontaining 1 to 3 carbon atoms;

U is an alkylene chain containing 1 to 3 carbon atoms, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

Q represents a divalent group of formula IIa, IIb or IIc

in which V is (CH₂)_(n), wherein n is 0, 1, 2 or 3, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

V′ is an alkylene chain containing 2 to 6 carbon atoms, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

E is an alkylene chain containing 0 to 2 carbon atoms and E′ is analkylene chain containing 1 to 4 carbon atoms provided that the totalnumber of carbon atoms in E and E′ amounts to 3 or 4;

R₅ and R₆, which may be the same or different, are H or an alkyl groupcontaining 1 to 4 carbon atoms; and

T represents phenyl, 1- or 2-naphthyl,1-naphth[2,1-d][1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2-, 3- or4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each ofwhich may be optionally substituted by one or more substituents selectedfrom a) halo, b) an alkyl group containing 1 to 4 carbon atomsoptionally substituted by one or more halo, c) an alkoxy groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, d) an alkylthio group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, e) hydroxy, f) an acyloxy groupcontaining 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) analkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonylgroup containing 2 to 6 carbon atoms, k) a carbamoyl group orcarbamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, l) a sulphamoyl orsulphamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, m) an amino group optionallysubstituted by one or two alkyl groups each containing 1 to 5 carbonatoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido.

In preferred compounds of formula I, A is —O—.

In preferred compounds of formula I, B is —O—.

In more preferred compounds of formula I, both A and B are —O—.

In preferred compounds of formula I, g is 0 or 1. When g is 1, R₁ ispreferably halo or an alkyl group containing 1 to 3 carbon atoms. Inmore preferred compounds of formula I, g is 0.

In preferred compounds of formula I, G₁—G₂—G₃ are —NH—CH═CH—; —O—CH═CH—;or —S—C(R″)═C(R′″)—. Preferably, R″ is H and R′″ is H or halo (morepreferably chloro). More preferably G₁—G₂—G₃ are —NH—CH═CH—; or—S—C(R″)═C(R′″)—.

In preferred compounds of formula I, R₂ is H.

In preferred compounds of formula I, R₃ and R₄, are both H.

In preferred compounds of formula I, U is methylene.

In preferred compounds of formula I, Q is a group of formula IIc inwhich V is methylene, E and E′ are both ethylene and R₆ is H.

In preferred compounds of formula I, T is phenyl or 2-, 3- or 4-pyridyleach of which may be optionally substituted by one or more substituentsselected from methoxy, nitro, halo or acetamido. In more preferredcompounds of formula I, T is 2-pyridyl or 4-acetamidophenyl.

In one group of preferred compounds of formula I, both A and B are —O—;g is 1, R₁ is halo or an alkyl group containing 1 to 3 carbon atoms;G₁—G₂—G₃ are —NH—CH═CH—; —O—CH═CH— or —S—C(R″)═C(R′″)—; R″ is H and R′″is H or halo; R₂ is H; R₃ and R₄, are both H; U is methylene; Q is agroup of formula IIc in which V is methylene, E and E′ are both ethyleneand R₆ is H; and T is phenyl or 2-, 3- or 4 pyridyl each of which may beoptionally substituted by one or more substituents selected frommethoxy, nitro, halo or acetamido.

In second group of preferred compounds of formula I, both A and B are—O—; g is 1, R₁ is halo or an alkyl group containing 1 to 3 carbonatoms; G₁—G₂—G₃ are —NH—CH═CH—; or —S—C(R″)═C(R′)—; R″ is H and R′″ is Hor halo; R₂ is H; R₃ and R₄, are both H; U is methylene; Q is a group offormula IIc in which V is methyene, E and E′ are both ethylene and R₆ isH; and T is phenyl or 2-, 3- or 4 pyridyl each of which may beoptionally substituted by one or more substituents selected frommethoxy, nitro, halo or acetamido.

Compounds of formula I may exist as salts with pharmaceuticallyacceptable acids. Examples of such salts include hydrochlorides,hydrobromides, sulphates, methanesulphonates, nitrates, maleates,acetates, citrates, fumarates, tartrates [eg (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures],succinates, benzoates and salts with amino acids such as glutamic acid.Compounds of formula I and their salts may exist in the form of solvates(for example hydrates).

It will be understood that any group mentioned herein which contains achain of three or more atoms signifies a group in which the chain may bestraight or branched. For example, an alkyl group may comprise propyl,which includes npropyl and isopropyl, and butyl, which includes n-butyl,sec-butyl, isobutyl and tert-butyl. The term ‘halo’ as used hereinsignifies fluoro, chloro, bromo and iodo.

Compounds of formula I and intermediates in their preparation containone or more chiral centres, and exist in different optically activeforms. When compounds of formula I and intermediates in theirpreparation contain one chiral centre, the compounds exist in twoenantiomeric forms and the present invention includes both enantiomersand mixtures of enantiomers. The enantiomers may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallisation; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallisation, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesised by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral centre it mayexist in diastereoisomeric forms. The diastereoisomeric pairs may beseparated by methods known to this skilled in the art, for examplechromatography or crystallisation and the individual enantiomers withineach pair may be separated as described above. The present inventionincludes each diastereoisomer of compounds of formula I and mixturesthereof.

Certain compounds of formula I and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof.

Certain compounds of formula I and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Specific compounds of formula I are:

N-{[1-(9-chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4]methyl}pyridine-2-sulphonamide;

N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}pyridin-2-sulphonamide;

4-acetamido-N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide;

N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide

N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-3-sulphonamide

2,3-dichloro-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide

N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}-2,4-difluorobenzenesulphonamide

4-(acetamido)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4benzodioxin-2-ylmethyl)piperid-4-yl}methyl)benzenesulphonamide

and pharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates, or other mixtures of enantiomers.

Specific enantiomeric forms of compounds of formula I include:

(S)-N-{[1-(9-chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide;

(S)-N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}-pyridine-2-sulphonamide;

(S)-4-acetamido-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide;

(S)-N-{[1-(2,3-dihydrofuro[3,2-f]1f[1,4)benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide

(S)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-3-sulphonamide

(S)-2,3-dichloro-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide

(S)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}-2,4-difluorobenzenesulphonamide

(S)-4-(acetamido)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide

and pharmaceutically acceptable salts thereof.

The present invention also includes pharmaceutical compositionscontaining a therapeutically effective amount of a compound of formula Ior a salt thereof together with a pharmaceutically acceptable diluent orcarrier.

As used hereinafter, the term “active compound” denotes a compound offormula I or a salt thereof. In therapeutic use, the active compound maybe administered orally, rectally, parenterally or topically, preferablyorally. Thus the therapeutic compositions of the present invention maytake the form of any of the known pharmaceutical compositions for oral,rectal, parenteral or topical administration. Pharmaceuticallyacceptable carriers suitable for use in such compositions are well knownin the art of pharmacy. The compositions of the invention may contain0.1-99% by weight of active compound. The compositions of the inventionare generally prepared in unit dosage form. Preferably the unit dosageof active ingredient is 1-500 mg. The excipients used in the preparationof these compositions are the excipients known in the pharmacist's art.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, syrups and aqueous or oilsuspensions. The excipients used in the preparation of thesecompositions are the excipients known in the pharmacist's art. Tabletsmay be prepared by mixing the active compound with an inert diluent suchas calcium phosphate in the presence of disintegrating agents, forexample maize starch, and lubricating agents, for example magnesiumstearate, and tableting the mixture by known methods. The tablets may beformulated in a manner known to those skilled in the art so as to give asustained release of the compounds of the present invention. Suchtablets may, if desired, be provided with enteric coatings by knownmethods, for example by the use of cellulose acetate phthalate.Similarly, capsules, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, may beprepared by conventional means and, if desired, provided with entericcoatings in a known manner. The tablets and capsules may convenientlyeach contain 1 to 500 mg of the active compound. Other compositions fororal administration include, for example, aqueous suspensions containingthe active compound in an aqueous medium in the presence of a non-toxicsuspending agent such as sodium carboxymethyl-cellulose, and oilysuspensions containing a compound of the present invention in a suitablevegetable oil, for example arachis oil.

The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for examplewater) before ingestion. The granules may contain disintegrants (forexample a pharmaceutically acceptable effervescent couple formed from anacid and a carbonate or bicarbonate salt) to facilitate dispersion inthe liquid medium.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for example,suppositories with cocoa butter or polyethylene glycol bases.

Pharmaceutical compositions may also be administered parenterally (forexample subcutaneously, intramuscularly, intradermally and/orintravenously [such as by injection and/or infusion]) in the knownpharmaceutical dosage forms for parenteral administration (for examplesterile suspensions in aqueous and/or oily media and/or sterilesolutions in suitable solvents, preferably isotonic with the blood ofthe intended patient). Parenteral dosage forms may be sterilised (forexample by micro-filtration and/or using suitable sterilising agents[such as ethylene oxide]). Optionally one or more of the followingpharmaceutically acceptable adjuvants suitable for parenteraladministration may be added to parenteral dosage forms: localanaesthetics, preservatives, buffering agents and/or mixtures thereof.Parenteral dosage forms may be stored in suitable sterile sealedcontainers (for example ampoules and/or vials) until use. To enhancestability during storage the parenteral dosage form may be frozen afterfilling the container and fluid (for example water) may be removed underreduced pressure.

Pharmaceutical compositions may be administered nasally in knownpharmaceutical forms for such administration (for example sprays,aerosols, nebulised solutions and/or powders). Metered dose systemsknown to those skilled in the art (for example aerosols and/or inhalers)may be used.

Pharmaceutical compositions may be administered to the buccal cavity(for example sub-lingually) in known pharmaceutical forms for suchadministration (for example slow dissolving tablets, chewing gums,troches, lozenges, pastlles, gels, pastes, mouthwashes, rinses and/orpowders).

Compositions for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, for example paraffin wax or beeswax, together with apotential transdermal accelerant such as dimethyl sulphoxide orpropylene glycol. Alternatively the active compounds may be dispersed ina pharmaceutically acceptable cream or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

The compounds of the present invention may also be administered bycontinuous infusion either from an external source, for example byintravenous infusion or from a source of the compound placed within thebody. Internal sources include implanted reservoirs containing thecompound to be infused which is continuously released for example byosmosis and implants which may be (a) liquid such as a suspension orsolution in a pharmaceutically acceptable oil of the compound to beinfused for example in the form of a very sparingly water-solublederivative such as a dodecanoate salt or ester or (b) solid in the formof an implanted support, for example of a synthetic resin or waxymaterial, for the compound to be infused. The support may be a singlebody containing all the compound or a series of several bodies eachcontaining part of the compound to be delivered. The amount of activecompound present in an internal source should be such that atherapeutically effective amount of the compound is delivered over along period of time.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The present invention also comprises the use of a compound of formula Ias a medicament.

The compounds of formula I or salts thereof or pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof formula I or a salt thereof may be used to treat depression, anxiety,psychoses (for example schizophrenia), tardive dyskinesia, Parkinson'sdisease, obesity, hypertension, Tourette's syndrome, sexual dysfunction,drug addiction, drug abuse, cognitive disorders, Alzheimer's disease,senile dementia, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders, anorexia, cardiovascular and cerebrovasculardisorders, non-insulin dependent diabetes mellitus, hyperglycaemia,constipation, arrhythmia, disorders of the neuroendocrine system,stress, and spasticity in human beings. Whilst the precise amount ofactive compound administered in such treatment will depend on a numberof factors, for example the age of the patient, the severity of thecondition and the past medical history and always lies within the sounddiscretion of the administering physician, the amount of active compoundadministered per day is in the range 1 to 1000 mg preferably 5 to 500 mggiven in single or divided doses at one or more times during the day.

A further aspect of the present invention provides the use of a compoundof formula I in the manufacture of a medicament for treating depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimersdisease, senile dementia, obsessive-compulsive behaviour, panic attacks,social phobias, eating disorders and anorexia, cardiovascular andcerebrovascular disorders, non-insulin dependent diabetes mellitus,hyperglycaemia, constipation, arrhythmia, disorders of theneuroendocrine system, stress, or spasticity in human beings.

The present invention also provides a method of treating depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimersdisease, senile dementia, obsessive-compulsive behaviour, panic attacks,social phobias, eating disorders and anorexia, cardiovascular andcerebrovascular disorders, non-insulin dependent diabetes mellitus,hyperglycaemia, constipation, arrhythmia, disorders of theneuroendocrine system, stress, or spasticity in human beings whichcomprises the administration of a therapeutically effective amount of acompound of formula I to a patient in need thereof.

Processes for the preparation of compounds of formula I will now bedescribed. These processes form a further aspect of the presentinvention. The processes are preferably carried out at atmosphericpressure, at a temperature in the range 0-200° C., preferably in therange 20-150° C. The substituents are as defined for formula I aboveunless otherwise stated.

Compounds of formula I in which Q is a group of formula Ila in which R₅is H, and V is (CH₂)_(n) wherein n is 1, 2 or 3 may be prepared byreaction of a compound of formula III

in which m is 0, 1 or 2, with a compound of formula IV

in which Z is a leaving group, for example toluene-4-sulphonyloxy,optionally in the presence of a suitable solvent, for exampleacetonitrile, optionally in the presence of a base, for examplepotassium carbonate, and optionally in the presence of a catalyst, forexample potassium iodide.

Compounds of formula I in which U is methylene and Q is a group offormula lha in which R₅ is H, and V is (CH₂)_(n) wherein n is 1, 2 or 3,and R″ and R′″ are other than formyl may be prepared by reaction of acompound of formula V

with a compound of formula III, followed by reduction of theintermediate imine with a suitable reducing agent, for example sodiumborohydride.

Compounds of formula I in which Q represents a group of formula IIc inwhich R₆ is H and V is (CH₂)_(n) wherein n is 1, 2 or 3 may be preparedby reacting a compound of formula Va

in which m is 0, 1 or 2 with a compound of formula X—SO₂—T in which X isa leaving group, for example halo or hydroxy, in the presence of a base,for example triethylamine, in a suitable solvent such asdichloromethane.

Compounds of formula III may be prepared by reaction of a compound offormula VI

in which D is a protecting group, for example5-bromo-2-hydroxybenzylidene, and m is 0, 1 or 2, with a sulphonylatingagent of formula X—SO₂—T in which X is a leaving group, for example haloor hydroxy, in the presence of a base, for example triethylamine, in asuitable solvent such as dichloromethane, followed by removal of theprotecting group, for example by acid-catalysed hydrolysis.

Compounds of formula IV in which Z is toluene-4-sulphonyloxy may beprepared by reaction of a compound of formula VIII

with toluene-4-sulphonyl chloride, optionally in the presence of a base,for example pyridine.

Compounds of formula Va may be prepared by deprotecting a compound offormula Vb

in which D is a protecting group, for example by acid catalysedhydrolysis.

Compounds of formula Vb may be prepared by reacting a compound offormula IV with a compound of formula VI optionally in the presence of asuitable solvent, for example acetonitrile, optionally in the presenceof a base, for example potassium carbonate, and optionally in thepresence of a catalyst, for example potassium iodide.

Compounds of formula VI may be prepared by reaction of a compound offormula VII

in which m is 0, 1 or 2, with a protecting reagent, for example5-bromo-2-hydroxybenzaldehyde.

Compounds of formula VII in which A and B are both —O—, R₂, R₃ and R₄are all H, and U is methylene may be prepared by reaction of a compoundof formula IX

in which Z is a leaving group, for example chloro ortoluene-4-sulphonyloxy, with a compound of formula X

in a suitable solvent, for example water or dimethylformamide in thepresence of a base, for example sodium hydroxide. When the appropriateenantiomerically pure form of a compound of formula IX, for example(R)-glycidyl 4-toluenesulphonate, is used, the single (S)-enantiomer ofa compound of formula VII can be prepared.

Compounds of formula VIII in which A and B are both —O—, U is methylene,and R₂, R₃ and R₄ are all H, may also be prepared by cyclisation of acompound of formula XI

in which R is H or an alkyl group containing 1 to 4 carbon atoms, usinga base, for example potassium carbonate.

Compounds of formula VIII in which R″ is H or CO₂Et may be prepared bycyclisation of the appropriate compound of formula XI in the presence ofpotassium carbonate.

Compounds of formula VIII in which R″ is CO₂H may be prepared byhydrolysis of the corresponding compound of formula VIII in which R″ isCO₂Et.

Compounds of formula VIII in which R″ is H may also be prepared bydecarboxylation of the corresponding compound of formula VIII in whichR″ is CO₂H.

Compounds of formula VIII in which R″ is CONH₂ may be prepared byamination of the corresponding compound of formula VIII in which R″ isCO₂Et.

Compounds of formula VIII in which R″ is CONMe₂ may be prepared byamination of the corresponding compound of formula VIII in which R″ isCO₂Et.

Compounds of formula VIII in which R″ is CHO may be prepared byreduction of the corresponding compound of formula VIII in which R″ isCO₂Et.

Compounds of formula VIII in which R″ is COMe may be prepared byreaction of the corresponding compound of formula VIII in which R″ isCO₂H with methyl lithium.

Compounds of formula VIII in which R″ is CN may be prepared bydehydration of the corresponding compound of formula VIII in which R″ isCONH₂.

Compounds of formula XI may be prepared by oxidation of compounds offormula XII

in which R is H or an alkyl group containing 1 to 4 carbon atoms, with aperoxyacid, for example 3-chloroperoxybenzoic acid.

Compounds of formula XII may be prepared by alkylating compounds offormula XIII

in which R is H or an alkyl group containing 1 to 4 carbon atoms, withcompounds of formula IX, in which Z is a leaving group, for examplechloro or toluene-4-sulphonyloxy, in a suitable solvent, for exampledimethylformamide, in the presence of a base, for example potassiumcarbonate. When the appropriate enantiomerically pure form of a compoundof formula IX, for example (R)-glycidyl 4-toluenesulphonate, is used,the single (S)-enantiomer of a compound of formula VIII can be prepared.

Compounds of formula VIII in which A and U are methylene, B is —O—, R₂is H and R″ and R′″ are H or cyano, may be prepared by reduction of acompound of formula XIV

with a reducing agent, for example borane-dimethyl sulphide complex.

Compounds of formula XIV may be prepared by reduction of a compound offormula XV

in which L is H with a reducing agent, for example hydrogen in thepresence of a palladium-on-carbon catalyst.

Compounds of formula XV in which L is H may be prepared by acid orbase-catalysed hydrolysis of a compound of formula XV in which L is analkyl group containing 1 to 6 carbon atoms.

Compounds of formula XV in which L is an alkyl group may be prepared byreaction of a compound of formula XIII in which R is H with a compoundof formula XVI

in which L is an alkyl group containing 1 to 6 carbon atoms, in thepresence of a base, for example 1,4-diazabicyclo[2.2.2]octane (DABCO).

Compounds of formula V may be prepared by oxidation of a compound offormula VIII in which U is methylene with a suitable oxidising agent,for example pyridinium chlorochromate or by reduction of a compound offormula XVIII

with a suitable reducing agent, for example sodiumbis(2-methoxyethoxy)aluminium hydride in a solvent, for example toluene.

Compounds of formula XVII in which A and B are both —O— may be preparedby reaction of a compound of formula XVIII

in which Y is a leaving group, for example bromo, and L is an alkylgroup containing 1 to 6 carbon atoms with a compound of formula X, inthe presence of a base, for example potassium carbonate.

Compounds of formula XVII in which A is methylene, B is —O—, R₂ is H andL is an alkyl group containing 1 to 6 carbon atoms may be prepared byreduction of a compound of formula XV in which L is an alkyl groupcontaining 1 to 6 carbon atoms, with a suitable reducing agent, forexample hydrogen in the presence of a palladium-on-carbon catalyst.

Compounds of formula I in which Q is a group of formula lib may beprepared by reaction of a compound of formula IV in which Z is a leavinggroup, for example toluene-4-sulphonyloxy, with a compound of formulaXIX

in which D′ is H, optionally in the presence of a base, for examplepotassium carbonate, and optionally in a solvent, for exampleacetonitrile.

Compounds of formula XIX in which D′ is H may be prepared bydeprotection of a compound of formula XIX in which D′ is a protectinggroup, for example tert-butoxycarbonyl, for example by hydrolysis in thepresence of an acid, for example trifluoroacetic acid.

Compounds of formula XIX in which D′ is a protecting group may beprepared by reaction of a compound of formula XX

in which D′ is a protecting group, for example tert-butoxycarbonyl, witha compound of formula X—SO₂—T in which X is a leaving group, for examplehalo, alkoxy, hydroxy or alkoxycarbonyloxy, in the presence of a base,for example triethylamine, in a suitable solvent such asdichloromethane.

Compounds of formula I in which Q is a group of formula IIc in which Vis (CH₂)_(n) wherein n is 1, 2, or 3 may be prepared by reaction of acompound of formula XXI

in which D′ is H and m is 0, 1 or 2, with a compound of formula IV inwhich Z is a leaving group, for example toluene-4-sulphonyloxy,optionally in the presence of a base, for example potassium carbonate,and optionally in a solvent, for example acetonitrile.

Compounds of formula XXI in which D′ is H may be prepared bydeprotection of a compound of formula XXI in which D′ is a protectinggroup, for example tert-butoxycarbonyl, for example by hydrolysis in thepresence of an acid, for example trifluoroacetic acid.

Compounds of formula XXI in which D′ is a protecting group may beprepared by reaction of a compound of formula XXII

in which D′ is a protecting group, for example tert-butoxycarbonyl, andm is 0, 1 or 2, with a compound of formula X—SO₂—T in which X is aleaving group, for example halo or hydroxy, in the presence of a base,for example triethylamine, in a suitable solvent such asdichloromethane.

Compounds of formula IV in which G₁—G₂—G₃ are —NH—CH═CH— are known (J.Med. Chem.,1992,35, pg 3058).

Compounds of formula I in which R₅ is an alkyl group and R″ and R′″ areother than formyl may be prepared by alkylation of a compound of formulaI in which R₅ is H with for example formaldehyde and formic acid, or analdehyde and a reducing agent such as sodium cyanoborohydride.

Compounds of formula XIII in which R is H may be prepared by reaction ofa compound of formula XXIII

with an N-arylformimidate ester of formula XXIV

in which R^(a) is H, an alkyl group containing 1 to 3 carbon atoms, analkoxy group containing 1 to 3 carbon atoms, or halo, and R^(b) is analkyl group containing 1 to 3 carbon atoms, for example ethylN-(4-methoxyphenyl)formimidate, followed by hydrolysis of theintermediate imine in the presence of an acid. Compounds of formula IVin which G₁—G₂—G₃ are other than —NH—CH═CH— may be prepared by methodsanalogous to that described above.

The ability of compounds of formula I to interact with5-hydroxytryptamine (5-HT) receptors has been demonstrated by thefollowing test which determines the ability of the compounds to inhibittritiated ligand binding to 5-HT receptors in vitro and in particular to5-HT_(1A) receptors.

Hippocampal tissue from the brains of male Charles River CD ratsweighing between 150-250 g were homogenised in ice-cold 50 mM Tris-HClbuffer (pH 7.7) when measured at 25° C., 1:40 w/v) and centrifuged at30,000 g at 4° C. for 10 minutes. The pellet was rehomogenised in thesame buffer, incubated at 37° C. for 10 minutes and centrifuged at30,000 g at 4° C. for 10 minutes. The final pellet was resuspended in 50mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl₂, 0.1% L-ascorbic acidand 10 μM pargyline hydrochloride (equivalent to 6.25 mg wet weight oftissue/ml) and used immediately in the binding assay. Aliquots (400 μl;equivalent to 2.5 mg wet weight of tissue/tube) of this suspension wereadded to tubes containing the ligand (50 μl; 2 nM) and distilled water(50 μl; total binding) or 5-HT (50 μl; 10 4M; non-specific binding) ortest compound (50 μl; at a single concentration of 10⁻⁶ M or at 10concentrations ranging from 10⁻¹¹-10⁻³ M). The ligand was[³H]8-hydroxy-2-(dipropylamino)tetralin ([³H]-OH-DPAT) and the mixturewas incubated at 25° C. for 30 minutes before the incubation wasterminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Thefilters were punched out into vials, scintillation fluid added andradioactivity determined by liquid scintillation counting. Thepercentage displacement of specific binding of the tritiated ligand wascalculated for the single concentration (10⁻⁶ M) of test compound.Displacement curves were then produced for those compounds whichdisplaced ≧50% of specific binding of the tritiated ligand at 10⁻⁶ Musing a range of concentrations of the compound. The concentration whichgave 50% inhibition of specific binding (IC₅₀) was obtained from thecurve. The inhibition coefficient Ki was then calculated using theformula$K_{i} = \frac{IC50}{1 + \left( {\lbrack{ligand}\rbrack/K_{D}} \right)}$

in which [ligand] is the concentration of the tritiated ligand used andK_(D) is the equilibrium dissociation constant for the ligand.

The ability of compounds of formula I to interact with dopaminereceptors has been demonstrated by the following test which determinesthe ability of the compounds to inhibit tritiated ligand binding todopamine receptors in vitro and in particular to the D₂-like dopaminereceptors.

Striatal tissue from the brains of male Charles River CD rats weighingbetween 140-250 g were homogenised in ice-cold 50 mM Tris-HCl buffer (pH7.7 when measured at 25° C.) and centrifuged at 40,000 g for 10 minutes.The pellet was resuspended in Tris salts buffer (50 mM Tris-HCl buffercontaining 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂ and 1 mM MgCl₂ with theaddition of 6 mM ascorbic acid; pH 7.7 when measured at 25° C.), andagain centrifuged at 40,000 g for 10 minutes. The final pellet wasstored at −80° C. Before each test the pellet was resuspended in Trissalts buffer (equivalent to 2 mg wet weight of tissue/ml). Aliquots (720μl; equivalent to 1.44 mg wet weight of tissue/tube) of this suspensionwere then added to tubes containing the ligand (40 μl; 1 nM) and Trissalts buffer (40 μl; total binding) or spiroperidol (40 μl; 10 nM;non-specific binding) or test compound (40 μl; at a single concentrationof 10⁻⁶M or at 6 concentrations ranging from 10⁻¹¹-10⁻⁴M). The ligandwas tritiated (S)-sulpiride and the mixture was incubated at 4° C. for40 minutes before the incubation was terminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Thefilters were punched out in to vials, scintillation fluid added and wereleft for about 20 hours before being counted by scintillationspectrophotometry. The percentage displacement of specific binding ofthe tritiated ligand was calculated for the single concentration (10⁻⁶M)of test compound. Displacement curves were then produced over a range ofconcentrations for those compounds which displaced ≧50% of specificbinding of the tritiated ligand at 10⁻⁶M. The concentration which gave a50% inhibition of specific binding (IC50) was obtained from the curve.The inhibition coefficient Ki was then calculated using the formula$K_{i} = \frac{IC50}{1 + \left( {\lbrack{ligand}\rbrack/K_{D}} \right)}$

in which [ligand] is the concentration of the tritiated ligand used andK_(D) is the equilibrium dissociation constant for the ligand.

The K_(i) values obtained in the above tests for 5-HT_(1A) and D₂-likebinding for each of the final products of the Examples hereinafter aregiven in Table 1 below.

TABLE 1 Example Ki (nM) value for Number 5-HT_(1A) D₂-like 1 98% 106% 299% 105% 3 97% 105%

The % figures in Table 1 are for % displacement at 10⁻⁶M.

The invention is illustrated by the following Examples which are givenby way of example only. The final product of each Example wascharacterised by one or more of the following procedures: gas-liquidchromatography; high performance liquid chromatography; elementalanalysis, nuclear magnetic resonance spectroscopy and infraredspectroscopy.

EXAMPLE 1

A stirred solution of ethyl3-chloro-5-methoxybenzo[b]thiophene-2-carboxylate (20.0 g) indichloromethane (80 ml) at −20° C. under an atmosphere of nitrogen wastreated with boron tribromide (1M solution in dichloromethane; 90 ml)and the solution allowed to warm up to room temperature slowly. After 2hours the mixture was carefully poured into ethanol (400 ml) and left tostand for 10 minutes. The solvent was evaporated under reduced pressureand the residue dissolved in ethyl acetate (500 ml). The resultingsolution was washed with water (300 ml), dried over sodium sulphate andthe solvent evaporated under reduced pressure to give ethyl3-chloro-5-hydroxybenzo[b]thiophene-2-carboxylate (18.68 g) as anoff-white solid; m.p. 160-161° C.

A round bottomed flask containing a mixture of the product from theprevious reaction (6.04 g) and ethyl N-(4-methoxyphenyl)formimidate(4.50 g) was submerged rapidly in an oil bath pre-heated to 160° C., andthe mixture stirred at 160-80° C. for 4 hours, the ethanol produced inthe reaction being removed by distillation. More of the formimidate(0.80 g) was then added and the mixture heated at 180-90° C. for afurther 1 hour. The cooled mixture was then treated with boilingmethanol (100 ml) and the resulting light brown solid collected byfiltration, washed with methanol (100 ml) and dried to give ethyl3-chloro-5-hydroxy-4-[N-(4-methoxyphenyl)iminomethyl]benzo[b]thiophene-2-carboxylate(4.03 g); m.p. 162-163° C.

A stirred mixture of the product from the previous reaction (3.82 g) andhydrochloric acid (4M; 130 ml) was heated at 50-60° C. for 4 hours andthen left to stand at room temperature overnight. The mixture was thenheated at 60-70° C. for 3 hours. The cooled mixture was poured intowater (350 ml) and extracted with ethyl acetate (2×250 ml). The combinedorganic extracts were washed with water (200 ml), dried over sodiumsulphate and evaporated under reduced pressure to give ethyl3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (2.80 g) as apale-green solid; m.p. 128-130° C.

Potassium carbonate (2.62 g) was added to a stirred solution of ethyl3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (4.90 g,prepared as described above) in dry dimethylformamide (50 ml) and then asolution of (R)-glycidyl tosylate (4.12 g) in dry dimethyl formamide (50ml) was added slowly. The mixture was then stirred at 60° C. for 3hours, cooled and poured into water (1200 ml). The resulting pale-greensolid was collected by filtration, washed with water (200 ml) and driedto give ethyl(R)-3-chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]thiophene-2-carboxylate(5.15 g).

A stirred solution of the product from the previous reaction (1.0 g) indichloromethane (20 ml) was treated with 3-chloroperoxybenzoic acid(85%; 0.75 g) and the mixture cooled to 0° C. A solution oftrifluoroacetic acid (0.335 g) in dichloromethane (5 ml) was then addedand the solution stirred at 0° C. for 5 minutes and then at roomtemperature for 1 hour. The mixture was poured into saturated aqueoussodium bisulphite solution (100 ml) and extracted with dichloromethane(2-100 ml). The combined organic extracts were washed with saturatedaqueous sodium bicarbonate solution (2-150 ml), dried over sodiumsulphate and evaporated under reduced pressure to give a brown oil.Purification by flash chromatography on silica using a 1:1 mixture ofpetroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant gave ethyl(R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxybenzo[b]thiophene-2-carboxylate(0.52 g) as a pale-yellow solid.

Saturated aqueous potassium carbonate solution (20 ml) was added to astirred solution of ethyl(R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxy-benzo[b]thiophene-2-carboxylate(1.85 g, prepared as described above) in tetrahyrofuran (20 ml) and themixture stirred for 24 hours at room temperature. The reaction mixturewas poured into water (200 ml) and extracted with ethyl acetate (2×100ml). The combined extracts were dried over sodium sulphate andevaporated under reduced pressure to give a yellow solid. Purificationby flash chromatography on silica using a 1:1 mixture of petroleum ether(b.p. 60-80° C.) and ethyl acetate as eluant gave ethyl(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4]-benzodioxin-8-carboxylate(1.44 g) as a pale-yellow solid; m.p. 165-166° C.

A stirred solution of the product from the previous reaction (1.30 g) inmethanol (20 ml) was treated with a solution of lithium hydroxidemonohydrate (0.17 g) in water (10 ml) and the mixture heated at 60° C.for 1 hour. The solution was evaporated under reduced pressure to removemethanol and then diluted with water (50 ml). The aqueous solution wasacidified with hydrochloric acid (2 M) and the resulting suspensioncollected by filtration, washed with water and dried to give(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4]benzodioxin-8-carboxylicacid (1.15 g) as an off-white solid, m.p. 236-7° C.

A round bottomed flask containing a mixture of the product from theprevious reaction (0.80 g) , copper powder (0.17 g) and quinoline (10ml) was rapidly submerged in an oil bath pre-heated to 190° C., and themixture heated with stirring at this temperature for 30 minutes. Themixture was cooled to room temperature and poured into hydrochloric acid(2M; 300 ml). The mixture was extracted with ethyl acetate (2×150 ml)and the combined extracts washed with hydrochloric acid (2M; 150 ml) ,water (150 ml), then dried over sodium sulphate and evaporated underreduced pressure to give a dark brown oil (0.781 g). Purification byflash chromatography on silica using a 3:7 mixture of ethyl acetate andpetroleum ether (b.p. 60-80° C.) as eluant gave(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4]benzodioxin(0.58 g) as a fawn solid, m.p. 92-3° C.

A stirred solution of the product from the previous reaction (0.49 g) indichloromethane (20 ml) was treated with 4-(dimethylamino)pyridine (0.26g). 4-Toluenesulphonyl chloride (0.40 g) was then added and theresulting solution stirred for 24 hours at room temperature. Thereaction mixture was poured into water (100 ml) and extracted withdichloromethane (150 ml). The organic extract was washed successivelywith saturated copper sulphate solution (2×100 ml), water (100 ml),dried over sodium sulphate and evaporated under reduced pressure to give(S)-9-chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-ylmethyl4-toluenesulphonate (0.70 g) as a white solid, m.p. 1 69-70° C.

A stirred solution ofN-[(1-tert-butoxycarbonylpiperid-4-yl)methyl]pyridine-2-sulphonamide(0.20 g) in dichloromethane (10 ml) was treated with trifluoroaceticacid (2 ml) and the mixture stirred at room temperature for 2 hours. Themixture was evaporated under reduced pressure and the oily residuedissolved in dry acetonitrile (20 ml). Potassium carbonate (3.0 g) and asolution of the product from the previous reaction (0.095 g) in dryacetonitrile (10 ml) was then added and the mixture heated under refluxwith stirring for 24 hours. The cooled reaction mixture was filtered andthe solvent removed under reduced pressure. The residue was re-dissolvedin dichloromethane (200 ml) and washed with water (100 ml). The organicsolution was dried over sodium sulphate and evaporated under reducedpressure to give a yellow oil (0.15 g). Purification by flash columnchromatography on silica using a 95:5 mixture of dichloromethane andmethanol as eluant gave(S)-N{[1-(9-chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide(0.042 g) as a white solid.

EXAMPLE 2

A stirred solution ofN-[(1-tert-butoxycarbonylpiperid-4-yl)methyl]pyridine-2-sulphonamide(1.20 g) in dichloromethane (80 ml) was treated with trifluoroaceticacid (6 ml) and the mixture stirred at room temperature for 2 hours. Themixture was evaporated under reduced pressure and the oily residuedissolved in dry acetonitrile (50 ml). Potassium carbonate (6.0 g) and asolution of (S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl4-toluenesulponate (1.28 g) in dry acetonitrile (20 ml) was then addedand the mixture heated under reflux with stirring for 24 hours. Thecooled reaction mixture was filtered and the solid washed withdichloromethane (100 ml). The filtrate was evaporated under reducedpressure and the residue purified by flash chromatography on silicausing a 95:5 mixture of dichloromethane and methanol as eluant to give(S)-N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide0.075 dichloromethane solvate (0.58 g) as an off-white solid, m.p.86-88° C., [α]_(D)−39.3 (c=0.217, MeOH).

EXAMPLE 3

A stirred solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine(5.20 g) in dichloromethane (100 ml) was treated with triethylamine(5.31 g) and then 4-acetamidobenzenesulphonyl chloride (6.07 g) wasadded in small portions. The mixture was stirred at room temperature for4 hours and then left to stand for 72 hours. The mixture was poured intowater (200 ml) and extracted with dichloromethane (150 ml). The organicsolution was washed with hydrochloric acid (1M;100 ml) which led toprecipitation of a pale-yellow solid. The solid was collected byfiltration, dissolved in industrial methylated spirit (300 ml), driedover sodium sulphate and evaporated under reduced pressure to giveN-{[4-acetamido-1-(tert-butoxycarbonyl)-4-piperidyl]methyl}benzenesulphonamide(3.72 g) as a pale-yellow solid, m.p. 226-7° C.

A stirred solution of the product from the previous reaction (1.40 g) indichloromethane (30 ml) was treated with trifluoroacetic acid (4 ml) andthe solution stirred at room temperature for 2 hours. The mixture wasthen evaporated under reduced pressure and re-dissolved in dryacetonitrile (50 ml). Potassium carbonate (7.0 g) and a solution of(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl4-toluenesulphonate (1.20 g) in dry acetonitrile (20 ml) was then addedand the mixture heated under reflux with stirring for 24 hours. Thecooled mixture was filtered and the solid washed with dichloromethane(100 ml). The filtrate was then evaporated under reduced pressure andthe residue purified by flash column chromatography on silica using a9:1 mixture of dichloromethane and methanol as eluant to give apale-yellow solid which was triturated with diethyl ether to give(S)-4-acetamido-N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide0.75 hydrate (0.76 g) as an off-white solid, m.p. 133-4° C.,[α]_(D)−33.5° (c=0.257, EtOH).

EXAMPLE 4-8

Potassium carbonate (2.85 g), and a solution of (R)-glycidyl4-toluenesulphonate (4.50 g) in dry dimethylformamide (10 ml) were addedto a stirred solution of 5-hydroxybenzo[b]furan-4-carboxaldehyde (3.04g) in dry dimethylformamide (30 ml) . The mixture was heated at 60° C.for 2 hours and then poured into water (500 ml). The mixture wasextracted with dichloromethane (3×300 ml) and the combined extracts werewashed with water (8×200 ml), dried over sodium sulphate and evaporatedunder reduced pressure to give a red oil. Purification by flash columnchromatography on silica eluting with a 3:7 mixture of ethyl acetate andpetroleum ether (b.p. 40-60° C.) gave(R)-5-[2-(2,3-epoxypropoxy)]benzo[b]furan-4-carboxaldehyde (3.11 g) as ayellow solid m.p. 64-5° C.

3-Chloroperoxybenzoic acid (85%; 3.88 g) and a solution oftrifluoroacetic acid (1.61 g) in dichloromethane (5 ml) were added to astirred solution of the product from the previous reaction (3.08 g) indichloromethane (40 ml). The mixture was stirred at room temperature for30 minutes and poured into saturated aqueous sodium bisulphite (200 ml)then extracted with dichloromethane (2×150 ml). The combined extractswere washed with saturated aqueous s odium bicarbonate (3×350 ml), driedover sodium sulphate and evaporated under reduced pressure to give(R)-5-[2-(2,3-epoxypropoxy)]benzo[b]furan-5-yl formate (3.10 g) as a redoil.

Saturated aqueous potassium carbonate (15 ml) was added to a stirredsolution of the product from the previous reaction (3.09 g) intetrahydrofuran (30 ml) and the mixture stirred vigorously at roomtemperature for 72 hours. The mixture was poured into water (200 ml) andextracted with ethyl acetate (2×150 ml). The combined extracts weredried over sodium sulphate and evaporated under reduced pressure to givean orange oil. Purification by flash column chromatography on silicaeluting with a 2:3 mixture of ethyl acetate and petroleum ether (b.p.60-80° C.) gave(S)-2,3-dihydro-2-(hydroxymethyl)furn[3,2-f][1,4]benzodioxin (1.90 g) asa pale yellow oil.

4-Toluenesuephonyl chloride (1.89 g) was added to a stirred solution ofthe product from the previous reaction (1.86 g) in dichloromethane (40ml). 4-Dimethylaminopyridine (1.21 g) was then added and the resultingsolution stirred at room temperature for 18 hours. The mixture wasdiluted with dichloromethane (200 ml) and washed successively with water(100 ml), saturated aqueous copper sulphate solution (2×100 ml) andwater (100 ml). The organic solution was then dried over sodium sulphateand evaporated under reduced pressure to give(S)-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl4-toluenesulphonate (3.01 g) as a colourless oil.

In a similar manner to Example 3(S)-2,3-dihydrofuro[3,2-f]benzodioxin-2-ylmethyl 4-toluenesulphonate isreacted with an appropriate compound of formula III to give

EXAMPLE 4

(S)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide

EXAMPLE 5

(S)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-3-sulphonamide

EXAMPLE 6

(S)-2,3-dichloro-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide

EXAMPLE 7

(S)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}-2,4-difluorobenzenesulphonamide

EXAMPLE 8

(S)-4-(acetamido)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide.

Pharmaceutical Examples

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose are de-aggregated and blended. Themixture is filled into hard gelatin capsules, each capsule containing aunit dose or part of a unit dose of active compound.

b) Tablets

Tablets are prepared from the following ingredients.

Parts by weight Active compound 10 Lactose 190  Maize starch 22Polyvinylpyrrolidone 10 Magnesium stearate  3

The active compound, the lactose and some of the starch arede-aggregated, blended and the resulting mixture is granulated with asolution of the polyvinylpyrrolidone in ethanol. The dry granulate isblended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

Enteric Coated Tablets

Tablets are prepared by the method described in (b) above. The tabletsare enteric coated in a conventional manner using a solution of 20%cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of activecompound is incorporated in 1300 parts by weight of triglyceridesuppository base and the mixture formed into suppositories eachcontaining a therapeutically effective amount of active ingredient.

What is claimed is:
 1. Compounds of formula I

including enantiomers and pharmaceutically acceptable salts thereof inwhich A is methylene or —O—; B is methylene or —O—; G₁—G₂—G₃ represent—N(R′)—C(R′)═N—, —N═C(R″)—N(R′)—, —N(R′)—C(R″)═C(R′″)—,—C(R′″)═C(R″)—N(R′)—, —N(R′)—N═C(R″)—, —C(R″)═N—N(R′)—, —N(R′)—N═N—,—N═N—N(R′)—, —N═C(R″)—O—, —N═C(R″)—S—, —O—C(R″)═N—, —S—C(R″)═N—,—O—N═C(R″)—, —S—N═C(R″)—, —C(R″)═N—O—, —C(R″)═N—S—, —S—C(R″)═C(R′″)—,—C(R″)═C(R′″)—S—, —O—C(R″)═C(R′″)—, —C(R″)═C(R′″)—O— or —O—C(R′)(R′)—O—;R′ is H or an alkyl group containing 1 to 3 carbon atoms; R″ and R′″,which are the same or different, are H; halo; an alkyl group containing1 to 3 carbon atoms optionally substituted by one or more halo; carboxy;an alkanoyl group containing 1 to 6 carbon atoms; an alkoxycarbonylgroup in which the alkoxy group contains 1 to 3 carbon atoms; formyl;cyano; or a carbamoyl group or carbamoylmethyl group each optionallyN-substituted by one or two alkyl groups, which may be the same ordifferent, each containing 1 to 3 carbon atoms; g is 0, 1 or 2; R₁represents an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo; an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo; halo; or analkylthio group containing 1 to 3 carbon atoms optionally substituted byone or more halo; the substituents represented by R₁ being the same ordifferent when g is 2; R₂ is H or an alkyl group containing 1 to 3carbon atoms; R₃ and R₄, which are the same or different, are H, or analkyl group containing 1 to 3 carbon atoms; U is an alkylene chaincontaining 1 to 3 carbon atoms, optionally substituted by one or morealkyl groups each containing 1 to 3 carbon atoms; Q represents adivalent group of formula IIa, IIb or IIc

in which V is (CH₂)_(n), wherein n is 0, 1, 2 or 3, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms; V′ is an alkylene chain containing 2 to 6 carbon atoms,optionally substituted by one or more alkyl groups each containing 1 to3 carbon atoms; E is an alkylene chain containing 0 to 2 carbon atomsand E′ is an alkylene chain containing 1 to 4 carbon atoms provided thatthe total number of carbon atoms in E and E′ amounts to 3 or 4; R₅ andR₆, which may be the same or different, are H or an alkyl groupcontaining 1 to 4 carbon atoms; and T represents phenyl, 1- or2-naphthyl, 1-naphth[2,1-d][1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-,4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2-, 3- or4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each ofwhich may be optionally substituted by one or more substituents selectedfrom a) halo, b) an alkyl group containing 1 to 4 carbon atomsoptionally substituted by one or more halo, c) an alkoxy groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, d) an alkylthio group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, e) hydroxy, f) an acyloxy groupcontaining 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) analkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonylgroup containing 2 to 6 carbon atoms, k) a carbamoyl group orcarbamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, I) a sulphamoyl orsulphamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, m) an amino group optionallysubstituted by one or two alkyl groups each containing 1 to 5 carbonatoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido. 2.Compounds of formula I, as claimed in claim 1, in which both A and B are—O—; g is 1, R₁ is halo or an alkyl group containing 1 to 3 carbonatoms; G₁—G₂—G₃ are —NH—CH═CH—; or —S—C(R″)═C(R′″)—; R″ is H and R′″ isH or halo; R₂ is H; R₃ and R₄, are both H; U is methylene; Q is a groupof formula IIc in which V is methylene, E and E′ are both ethylene andR₆ is H; and T is phenyl or 2-, 3- or 4 pyridyl each of which may beoptionally substituted by one or more substituents selected frommethoxy, nitro, halo or acetamido.
 3. Compounds of formula I, as claimedin claim 1, selected from:N-{[1-(9-chloro-2,3-dihydrothieno[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide;N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamide;4-acetamido-N-{[1-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamide;N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-2-sulphonamideN-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}pyridine-3-sulphonamide2,3-dichloro-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamideN-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}-2,4-difluorobenzenesulphonamide4-(acetamido)-N-{[1-(2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl)piperid-4-yl]methyl}benzenesulphonamideand pharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates, or other mixtures of enantiomers.
 4. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, as claimed in claim 1, in conjunction with apharmaceutically acceptable diluent or carrier.
 5. A method of treatingdepression, anxiety, psychoses, tardive dyskinesia, Parkinson's disease,obesity, hypertension, Tourette's syndrome, sexual dysfunction, drugaddiction, drug abuse, cognitive disorders, Alzheimer's disease, seniledementia, obsessive-compulsive behaviour, panic attacks, social phobias,eating disorders and anorexia, cardiovascular and cerebrovasculardisorders, non-insulin dependent diabetes mellitus, hyperglycaemia,constipation, arrhythmia, disorders of the neuroendocrine system,stress, or spasticity in human beings, which comprises theadministration of a therapeutically effective amount of a compound offormula I, as claimed in claim 1, to a patient in need thereof.
 6. Aprocess for the preparation of compounds of formula I, as claimed inclaim 1, in which Q is a group of formula IIc, comprising the reactionof a compound of formula

in which D′ is H and m is 0, 1 or 2, with a compound of formula IV

in which Z is a leaving group, optionally in the presence of a base, andoptionally in a solvent.